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Summary of "Stem cell therapy for human neurodegenerative disorders - how to make it work" Satya Yerrabolu Parkinson's Disease Viability Characterized by the degeneration of dopaminergic neuronsStem cell grafts have been shown to normalize dopamine release and become fully integrated into neuronal circuitriesA problem that can arise though is dyskinesias, which adversely affects motor function Background Foremost, a definitive cause for Parkinson's Disease has not been found yet; however, multiple theories existOne theory focuses on Lewy bodies. Lewy bodies are abnormal conglomerations of proteins in nerve cells that can hinder the proper function of dopaminergic neurons, which are regularly associated with voluntary movement and behaviorAnother theory focuses on calbindin, which is a protein that protects dopamine from toxins in the brain. The lack of calbindin in neurons is proposed as a possible contributor to Parkinson's Disease Stroke ALS and Huntington's Stem Cell Neurons in PD Stem cells can form dopaminergic neuronsPrevious studies have shown that mouse and monkey ESCs and NSCs have formed dopaminergic-like neuronsFetal mesencephalic grafts contain cells that are about 5-10% dopaminergicThe picture above summarizes a variety of processes in which stem cells may generate functional neuronal cells Lindball, O., Kokaia, Z., Martinez-Serrano, A. (2004) Stem cell therapy for human neurodegenerative disorder-how to make it work, Nature Medicine, 10, S42-S50. Results Embryonic stem cells can form dopaminergic neurons in a variety of ways (seen in the figure above)Surgery-controlled trials were not very successfulGrafted cells did not survive and the secon resulted in degenerative changes. There was also a high chance of immune rejectionOther trials resulted in dskynesia (7-15% of grafts), which is a movement disorder caused by irregular amount of dopamine. Stem Cell Therapy Stem cell therapies for PD have to address a few key issues:Dyskinesia suppressionMobility improvementsLong-lasting survivalGrafts should become refined so that they can be close to the area of damage and fully repair the brainCancer formation needs to be avoidediPs cells?Could remove the issue of immune rejection Stroke and ESCs The blockage of an artery leads to focal ischemia in a CNS region in strokeDifferent neurons and glial cells degenerateStudies showed that grafts corresponded with an increase in metabolic activity and were successful Stem Cell Neurons Neurons were generated; however, they did not survive for a very long timeThe addition of FGF-2, EGF, stem cell factor, caspase inhibitors, and anti-inflammatory drugs has been shown to increase the lifespan of newly-formed neurons Stem Cell Therapy Only a small amount of neurons and associated circuitries occurs after ESC treatmentTo deal with this, developmental mechanisms must be explored to ensure that SCs will differentiate into fully functional cellsTransplantation may have to be coupled with stimulation of neurogenesis from endogenous NSCs ALS and ESCs ALS is characterized by progressive dysfunction and degeneration of motor neurons in the cerebral cortex, brain stem, and spinal cordESCs must target both upper and lower motor neuronsESC grafts have shown slight beneficial effects in mice, but they were probably not caused by neuronal differentiationA lot of research still needs to be performed Huntington's and ESCs Characterized by chorea and dementiaGrafts have generated sufficient reconstruction of circuitries Extent of clinical benefit from these trials was not determinedFuture therapies will have to ensure longer survival of grafted cells